Total process for making 13-hydrocarbon substituted gonapolyene - 17 - one compounds and intermediates produced in the course of the process

ABSTRACT

A COMPOUND HAVING A 16-(ETHERIFIED OR ESTERIFIED HYDROXY)-17-ACYLOXY-13-SUBSTITUTED GONA-1,3,5(10),8,14PENTAENE NUCLEUS IS OBTAINED BY ALLOWING A COMPOUND HAVING A 17-ACYLOXY-13-SUBSTITUTED 8,14-SECOGONA-1,3,5 (10),9(11),15-PENTAENE-14-ONE NUCLEUS TO CONTACT WITH AN ACID CATALYST IN PRESENCE OF ALCOHOL, PHENOL OR FATTY ACID, AND CONVERTING THE RESULTANT COMPOUND HAVING A 16-(ETHERIFIED OR ESTERIFIED HYDROXY)-17-ACYLOXY-13-SUBSTITUTED GONA-1,3,5(10),8,14-PENTAENE NUCEUS DIRECTLY OR AFTER REDUCTION OF ITS DOUBLE BOND AT THE 8-POSITION OR BANDS AT THE 8- AND 14-POSITIONS, TO A COMPOUND HAVING A 13-(HYDROCARBON SUBSTITUTED)GONAPOLYEN-17-ONE NUCLEUS. IT IS THUS MADE POSSIBLE TO EFFECT THE TOTAL SYNTHESIS OF THE GONA POLYENES (E.G. ESTRONE) VIA A LESSER NUMBER OF STEPS THAN HAS HERETOFORE BEEN POSSIBLE.

United States Patent O 3,579,544 TOTAL PROCESS FOR MAKING 13-HYDROCAR-BON SUBSTITUTED GONAPOLYENE 17 ONE COMPOUNDS AND INTERMEDIATES PRO-DUCED N THE COURSE OF THE PROCESS Kentaro Hiraga, Ikeda, TsunehikoAsako, Suita, and Takuichi Miki, Amagasaki, Japan, assignors to TakedaChemical Industries, Ltd., Osaka, Japan No Drawing. Filed May 24, 1968,Ser. No. 731,968 Claims priority, application Japan, May 24, 1967,42/312,973; May 25, 1967, ll/33,238 Int. Cl. C07c 169/08 US. Cla260397.5 9 Claims ABSTRACT OF THE DISCLOSURE A compound having al6-(etherified or esterified hydroxy)-17-acyloxy-13 substitutedgona-l,3,5(l),8,l4- pentaene nucleus is obtained by allowing a compoundhaving a 17-acyloxy-13-substituted 8,l4-secogona-l,3,5(10),9(11),15-pentaene-14-one nucleus to contact with an acid catalystin presence of alcohol, phenol or fatty acid, and converting theresultant compound having a l6-(etherified or esterifiedhydroxy)-17-acyloxy-l3-substituted gona-1,3,5(l0),8,14-pentaene nucleus,directly or after reduction of its double bond at the 8-position orhands at the 8- and l4-positions, to a compound having a l3-(hydrocarbonsubstituted)gonapolyen-l7-one nucleus. It is thus made possible toeliect the total synthesis of the gona polyenes (e.g. estrone) via alesser number of steps than has heretofore been possible.

The present invention relates to a novel process for producing acompound having a gonapolyen-17-one nucleus substituted in theIii-position by a hydrocarbonyl residue, e.g. a lower alkyl, benzyl orphenyl radical, and to novel intermediates therefor. More concretely,this invention relates to an improved total synthesis of a compoundhaving a l3-(hydrocarbon snbstituted)gona-2,5 (10)-dien-l7-one nucleus,a compound having a 13-(hydrocarbon substituted) gona -l,3,5(10)-trien-l7-one nucleus or a compound having a 13 (hydrocarbonsubstituted)gona-1,3,5(10),8-tetraen-17-one nucleus and of novelintermediates therefor, e.g. a compound having a lfi-(etherified oresterified hydroxy 17-acyloxy-13-substituted g0na-1,3,5(10),8,14pentaene nucleus, a compound having a 16-(etherified or esterifiedhydroxy-17- acyloxy)-13-substituted gona-l,3,5(10),8-tetraene nucleus, acompound having a l6-(etherified or esterified hydroxy)-17-(hydroxy oracyloxy)-13-substituted gona-l,3, (10)-triene nucleus, a compound havinga l6-(etherified or esterified hydroxy)-17-(hydroxy or acyloxy)-13-substituted gona-2,5,()-diene nucleus, all of which have a hydrocarbonresidue at the position 13 as a substituent.

The reason why partial synthesis has overwhelmed total synthesis inindustrial production of steroids is attributable mainly to diflicultyin treating a number of diastereoisomers which are concomitantly formedeither at the cyclization to form the steroid skeleton or at thesaturation of the unsaturated bonds.

Recently, more improved total synthesis of 19-norsteroids have beenreported independently by Smith et a1.

ice

(Experientia, 19, 394-396 (1963, No. 8), Windholz et al. (Journal ofOrganic Chemistry, 28, 1092-1094 (1963)), Miki et a1. (Proceedings ofthe Chemical Society, May 1963, 139) and Crispin et al. (ibid., January1963, 22). Although these processes brought hope of realizing anindustrial total synthesis of steroids, the processes are stillaccompanied by some ditficulties, one of which is that the processesinvolve very long series of steps, and another is that 2-substitutedcyclopentane- 1,3-dione, one of the starting compounds of theseprocesses, is rather expensive.

The present invention is based upon unexpected discoveries that acompound having a 16-(etherified or esterifiedhydroxy)-17-acyloxy-13-substituted gone-1,3,5 (10),8,14-pentaene nucleuscan readily be produced by allowing a compound having al7-acyloxy-13-substituted 8,14secogona-l,3,5(10),9(l1),15-pentaen-14-onenucle us to contact with an acid catalyst in the presence of alcohol,phenol or fatty acid, and by converting the soobtained compound having a16-(etherified or esterified hydroxy)-17-acyloxy-13-substituted gona-1,3,5 10) ,8,14- pentaene nucleus, directly or after reduction of itsdouble bond at the 8-position or bonds at the 8- and 14-positions, to acompound having a 13-(hydrocarbon substituted)gonapolyen-17 one nucleus:i.e. a compound having a 13 (hydrocarbon snbstituted)gona 2,5(10dien-l7-one nucleus, a compound having a 13-(hydrocarbonsubstituted)gona-1,3,5(10)-trien-17-one nucleus and a compound having a13-(hydrocarbon substituted) gona- 1,3,5(10),8-tetraen-17 one nucleus;see accompanying chart.

Owing to these discoveries, it is made possible to save one step in thetotal synthesis of the gona polyenes (e.g. estrone). For example,estrone can be prepared through 7 steps starting from the compounds (I)and (II) in the present process, while the known process requires 8steps starting from the same compounds. Besides, the optical resolutionprocess which is inevitable in the known process can be saved, whenoptically active 17-hydroxy-13- (hydrocarbon substituted)-8,14-secogona-l,3, 10) ,9(l1), 15-pentaen-14-one compound is employed,said compound being prepared by the microbiological reduction of thecarbonyl at position 17 of the corresponding 14,17- dione compound.Furthermore, the present invention makes it possible to employ4-hydroxy-2-(hydrocarbon substituted)cyclopentane-1,3-dione, which isreadily obtained from the corresponding 1,3,4-trione in a high yield(Journal of American Chemical Society, 65, 2296 (1943)), instead of the2-substituted-cyclopentane-1,3- dione which has been used in the knowntotal synthesis of steroids, and which is prepared only in a very lowield.

y One of the objects of the present invention is therefore to provide aprocess for producing a compound having a 16-(etherified or esterifiedhydroxy)-l7-acyloxy-13- (hydrocarbon substituted) gona 1,3,5(10),8,14-pentaene nucleus directly from a compound having a 17-acyloxy-13-(hydrocarbon substituted) 8,14-secogona-l,3,5(10),9(ll),l5-pentaen-14-one nucleus. v

Another object of this invention is to provide a process for producing acompound having a Iii-(hydrocarbon snbstituted)gonapoly(di, tri ortetra)en-17-one nucleus starting from a compound having aIii-(hydrocarbon substituted)-8,14-secogona 1,3,5 10),9(11),15 pentaene-14,17-dione nucleus.

Further object of this invention is to provide novel compounds having a16-(etherified or esterified hydroxy)- l7-acyloxy-13-(hydrocarbonsubstituted)gona 1,3,5(l), 8,14-pentaene nucleus, compounds having a16-(etherified or esterified hydroxy)-17-acyloxy 13 hydrocarbonsubstituted)gona 1,3,5 (l0),8 tetraene nucleus, compounds having al6-(etherified or esterified hydroxy)-l7- (hydroxy oracyloxy)-l3-(hydrocarbon substituted)gona- 1,3,5(10)-triene nucleus andcompounds having a 16- (etherified or esterified hydroxy)-l7-(hydroxy oracyloxy)13-(hydrocarbon substituted) gona 2,5 (10) diene nucleus.

Other objects will become apparent from the detailed descriptionhereinafter provided.

The first step of the present invention is the preparation of a compoundhaving a 17-hydroxy-l3fi-(hydrocarbon substituted) 8,14 secogona1,3,5(10),9(11),l5- pentaen-14-one nucleus(IV), for example, bysubjecting a compound having a 13-(hydrocarbon substituted)-8,14-secogona-1,3,5(l0),9(11),15 pentaene 14,17 dione nucleus (HI) toso-called Merrwein-Pondorf-Verley reduction employing aluminum alkoxide(e.g. aluminum isopropoxide, phenoxide, etc.) in a solvent such asmethanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane,ether, petroleum ether, chloroform, benzene, toluene, dimethyl formamideor pyridine at a temperature of about 60 C. to about 85 C., or bysubjecting the same compound to a biological selective reductionemploying a microorganism belonging to the genus Saccharomyces (e.g. S.carlsbergensis, S. pastorianus), the genus Candida (e.g. C. solani), thegenus Debaryomyces (e.g. D. villi, D. vanriiz'), the genus Kloeckera(e.g. K. magrza, etc.), the genus Pichia (e.g. P. wickerhamii, P.pijperi), the genus Petasospora (e.g. P. chambardi), the genusTorulopsis (e.g. T. gropengiesseri, T. famata) or the genus Hansenula(e.g. H. winger, H. holstii, H. capsulata).

The above-mentioned compound having a 13-(hydrocarbon substituted) 8,14secogona-1,3,5(l0),9(1l),15- pentaene-14,17-dione nucleus represented bythe formula:

wherein R is hydrogen, hydroxyl, etherified hydroxyl radical (e.g.methoxy, ethoxy, benzyloxy), or esterified hydroxyl radical (e.g.acetoxy, benzoyloxy, nicotinoyloxy), and R is a hydrocarbon residue,which is exemplified by a lower alkyl (e.g. methyl, ethyl, n-pro-pyl,isopropyl, n-butyl and isobutyl), phenyl or benzyl, and/or, at one ormore of the positions 1,2 and 4 in the skeleton, by a hydroxyl group, anetherified hydroxy group (e.g. methoxy, ethoxy, n-propoxy and n-butoxy),an esterified hydroxyl group (e.g. acetoxy, propionyloxy andbenzoyloxy), a halogen (e.g. fluorine and chlorine), a thio group (e.g.mercapto, methylthio, ethylthio and acetylthio) and an acyl group (e.g.acetyl, propionyl and benzoyl), and/ or at the position 15 in theskeleton, the hydrogen atom may further be replaced by a hydrocarbonresidue as exemplified above.

The compound (III) is prepared by, for example, a condensation reactionbetween a compound having a 4-hydroxy-Z-(hydrocarbonsubstituted)cyclopentane-1,3-dione nucleus (I) on one hand and acompound having a 2-(1'- hydroxy 1' tetralino)-ethylene (Ila) orS-(2-(1'-tetraliden) ethyl thiuronium (IIb) nucleus on the other hand,to

(Ill) give the compound having a 8,14-secogona-1,3,5(l0),9 (ll),l5-pentaene-l4,l7-dione nucleus (III).

(Ila) (Ilb) wherein X is lower acyloxy radical (e.g. acetyloxy,propionyloxy), halogen (e.g. chlorine, bromine), C10 (S0 A2, and each ofR and R has the same meaning as above, and R is hydrogen or an acyl(e.g. acetyl, propionyl or ethoxycarbonyl).

The condensation reaction of the compounds (I) and (II) is carried outwith or without the use of a suitable solvent. The reaction isaccelerated by the presence of a basic catalyst. As advantageous basiccatalyst, there may be exemplified alkali metal hydroxide (e.g. sodiumhydroxide and potassium hydroxide), alkali metal carbonate (e.g. sodiumcarbonate, sodium hydrogen-carbonate, potassium carbonate and potassiumhydrogencarbonate), alkali metal acylate (e.g. sodium acetate andpotassium acetate), quaternary ammonium hydroxide (e.g. trimethyl benzylammonium hydroxide), tertiary amine (e.g. trimethylamine,triethylamine), anion exchange resin (e.g. strongly basic styrene-typecopolymer resin), metal alkoxide (e.g. sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide and magnesiumethoxide), alumina and a mixture of two or more thereof. Basic solvent,such as acid amide (e.g. dimethylforrnamide and dimethylacetamide), andamine (e.g. pyridine, collidine and aldehydecollidine) can be usedsolely or in combination with any other basic catalyst, not only as thecatalyst but also as the solvent for the reaction. Other desirablesolvents include, for example, methanol, ethanol, n-propanol,isopropanol, nbutanol, tetrahydrofuran, dioxane, ether, petroleum ether,chloroform, benzene, toluene and xylene, and any other solvent can beused in so far as it does not inhibit or disturb the desiredcondensation reaction. The reaction may proceed under cooling or at roomtemperature and may be accelerated by heating. Usually, it is convenientto carry out the reaction at the neighborhood of C. or under refluxingconditions. In order to have an equilibrium migrate towards anacceleration of the reaction, water produced in the course ofcondensation reaction can desirably be eliminated from the reactionmixture by heating or as its azeotropic mixture with the solvent used.For the same purpose, a basic or neutral dehydrating agent canbe allowedto coexist in the reaction system, the dehydrating agent beingexemplified by calcium oxide or so-called molecular sieve.Thus-obtained, compounds having a 13-(hydrocarbon substituted) 8,14secogona- 1,3,5(10), 9(11),l5-pentaene-l4,l7-dione nucleus areexemplified as follows:

8,l4-secoestra-1,3,5(10),9(11),15-pentanene-14,17-dione;

3-methoxy-8,14-secoestra-1,3,S(10),9(1l),15-pentaene- 14,17-dione;

3-ethoxy-8, l4-secoestral ,3,5 10) ,9 (1 l ,IS-pentaene- 14,17-dione;

13-ethyl-8,l4-secogona-1,3,5(l0),9(11),15-pentaene- 14,17-dione;

13-isopropyl-8,14-secogona-l,3,5(10),9(l1),15-pentaene- 14,17-dione;

The second step of the present process is an acylation of the compound(IV) employing a conventional acylating agent (i.e. aliphatic oraromatic acid or its reactive derivative, e.g. acetic acid, acetylchloride, benzoyl chloride, propionyl chloride, succinic acid anhydride,etc.), to obtain the l7-acyloxy compound represented by the formulawherein R is an acyl radical and each of R and R has the same meaning asmentioned above.

The third step of the present total synthesis is an intramolecularcyclization of the compounds (V), resulting in closure of the ring C togive the compound having a 16-(etherified or esterifiedhydroxy)-l7-acyloxy-13-(hydrocarbonsubstituted)gona-l,3,5(10),8,14-pentaene nucleus represented by theformula wherein R is the residue of an alcohol, phenol or fatty acid,and each of R R and R has the same meaning as the above.

The cyclization reaction is conducted by allowing the compound (V) tocontact with an acid catalyst in the presence of an alcohol (e.g.methanol, ethanol, butanol, isopropanol), a phenol (e.g. phenol,cresol), a fatty acid (e.g. acetic acid, propionic acid, butyric acid)or their mixture. The acid catalyst can be an inorganic acid oranhydride thereof (e.g. hydrochloric acid, sulfuric acid, phosphoricacid, phosphorus pentoxide and polyphosphoric acid), hydrogen salts orpartial esters of these polybasic inorganic acids (e.g. sodium hydrogensulfate, monosodium dihydrogen phosphate and monomethyl sulfate), theirpyridine complexes (e.g. pyridine-hydrobromic acid complex), sulfonicacids (e.g. methanesulfonic acid, ethanesulfonic acid, benzenesulfonicacid and toluenesulfonic acid), sulfonated styrene type cation exchangeresins, so-called Lewis acids (e.g. aluminum chloride, boron trifluorideand tin chloride), silica gel, etc.

This reaction does not require any solvent. However, the reaction can beeffected more smoothly by the use of a suitable solvent, such asbenzene, toluene, xylene, tetrahydrofuran, dibutyl ether, methanol,ethanol and propanol. This reaction is also accelerated by heating andtakes place easily under mild heating. The reaction is advantageouslycarried out in the range of about 60 C. to about C.

The fourth step of the present invention comprises selective reductionof the compound having a 16-(etherified or esterifiedhydroxy)-17-acyloxy-l3-hydrocarbon substituted) gona-1,3,5 l0),8,14-pentaene nucleus, desirably after hydrolysis of the said compoundin, per se, conventional manner (e.g. in the presence of an alkalineagent, for example, sodium hydroxide, potassium hydroxide, etc.), toproduce a compound having a 16-(etherified or esterifiedhydroxy)-l7-(hydroxy or acyloxy)-13-(hydrocarbonsubstituted)-gona-l,3,5(l0),8-tetraene nucleus represented by theformula:

OR B. l

wherein each of R R and R has the same meaning as mentioned above, and Rmeans hydrogen or R which has the same meaning as mentioned above.

The conversion of the compound (VI) to the compound -(VII) isconveniently effected by so-called catalytic reduction. For thispurpose, Raney nickel or palladium catalyst is advantageously used. Thereaction can be carried out in a suitable solvent which is exemplifiedby dioxane, tetrahydrofuran, ether, methanol, ethanol and acetic acid.The reaction usually takes place at an ambient temperature; but, ifrequired, it may be carried out at an elevated or lowered temperature.At any event, too drastic conditions should be avoided for thisreaction, since there may take place further hydrogenation at thepositions 8 and 9 which may result in a configuration of the hydrogen atthe position 8 which is opposite that of the natural steroids.

The conversion of the compound (VI) to the compound (VII) is alsoetfected by employing such reducing agent ashydrazine-hydrogen-peroxide, nickel-aluminium alloy and alkaline agent,etc. as well as by means of biological reduction.

Thus-prepared compound (VII) can be subjected to a further reduction tosaturate the double bond at the position 8.

The reduction is preferably carried out by allowing an alkali metal toreact with compound (VII) in liquid ammonia. The alkali metal may belithium, sodium and potassium, for example. The reaction is carried outin liquid ammonia or its mixture with an inert solvent. The inertsolvents for the purpose include, for example, ether, dioxane andtetrahydrofuran. Since the agent is rather violent, the reaction isusually brought about at a lowered temperature, e.g. below ambienttemperature to about 30 C. The acyloxy radical of the 17-position can beconverted to hydroxyl radical in the course of this reaction.

In this way, there is produced with a good yield a compound having a17-hydroxy-16-(etherified or esterified hy- 7 droxyl) 13 (hydrocarbonsubstituted) gona 1,3,5(l)- triene nucleus represented by the formula:

(V III) wherein each of R R and R has the same meaning as mentionedabove.

Thus-prepared compound (VIII), if desirable, after being acylated at thehydroxyl radical at the position 17, can be reduced to saturate thedouble bond at the aromatic ring to produce a compound having a16-(etherified or esterified hydroxyl) l3- (hydrocarbonSubstituted)-gona 2,5 (l0)-dien-17ol nucleus (IX). The reduction canadvantageously be carried out by allowing an alkali metal to react withcompound (VIII) in liquid ammonia containing a proton source such asalcohol having up to 6 carbon atoms (e.g. methanol, ethanol,tertiary-butanol), other conditions being the same as the above. In thesame manner as this reaction, the compound having al7-acyloxy-16-(etherified or esterified hydroxyl)-13-substituted-1,3,5(), S-tetraene nucleus (VII) can also be converted to the sameproduct (IX), and the double bond at the position 8 as well as thedouble bond on the aromatic ring saturated:

wherein each of R R and R has the same meaning as mentioned above.

Thus-obtained compounds (VII), (VIII) and (IX), if desired, after beingacylated at the 17-hydroxy1 radical, are converted respectively to thosecompounds having a 13 (hydrocarbon substituted) gona polyen-l7-onenucleus: i.e. a compound having a l3-(hydrocarbonsubstituted)gona-l,3,5(10),8-tetraen-l7-one nucleus (X), a compoundhaving a 13-(hydrocarbon substituted)gona-1,

3,5(10) trien 17 one nucleus (XI) and a compound having a 13(hydrocarbon substituted) gona 2,5(10)- dien-l7-one nucleus (XII), bytreating the compounds (VII), (VIII or (IX) with an acid reagent. Theacid reagent may be any of pyridine hydrochloride, quinolinehydrochloride, potassium hydrogensulfate, hydrogen iodide, hydrogenbromide and organic sulfonic acids, as well as aluminum chloride, borontrifiuoride and phosphoric anhydride and other Lewis acids. In contrastto the acid catalyst for use in the ring-closin g reaction mentionedabove, which need only be dehydrating, the acid reagent mentioned justabove must be de-alcoholating. This reaction takes place when thesteroid is contacted With the acid reagent having de-alcoholating actioneither in the presence or in the absence of a solvent. While thereaction proceeds at room temperature, it may be accelerated by heatingto 100 to 300 C. It is preferable that the reac tion be conducted in aninert gas such as nitrogen.

The above-mentioned reactions invariably proceed irrespective of whetheroptically active compounds or racemic compounds are involved.

It is to be understood that the following examples are solely for thepurpose of illustration and are not intended to be construed aslimitations of this invention, and that variations may be resorted toWithout departing from the spirit and scope of this invention. In theexamples, g. and ml. are gram(s) and milli1iter(s), respectively.Temperatures are all uncorrected, and percentages are all on the Weightbasis. Room temperature in this specification signifies about 15 toabout 30 C.

EXAMPLE 1 (1) 3-methoxy-8,l4-secoestra-l,3,5(10),9(11),15- pentaene-14,17-di0ne In 100 ml. of water is dissolved 2 g. ofS-(Z-(G-methoxyl-tetraliden) ethy1)thiuronium acetate, followed by theaddition of 1 g. of 4-hydroxy-2-methylcyclopentane-1,3- dione. Themixture is stirred at room temperature for 3 hours, at the end of whichperiod the reaction mixture is extracted with ether. The ether extractis washed with water and dried, followed by evaporation of ether to give1 g. of 3-methoxy-8,l4-secoestra-1,3,5( 10),9(l l),l5pentaene-i4,17-dione in the form of yellow crystals.

( 2) 3-methoxy-17-hydroxy-8,14-secoestral,3,5(10),9(l1),l5-pentaen-14-one 6 g. ofaluminum isopropoxide is added to a solution of l g.3-rnethoxy-8,14-secoestra-1,3,5(10),9(1l),l5-pentaene-14,17-dione in 100ml. of isopropanol, and the mixture is heated at about C. with agitationfor one hour while evaporating acetone(by-product) and isopropanol(solvent) little by little. To the reaction mixture is added an aqueoussolution of Rochelle salt (sodium potassium tartrate) and the mixture isextracted with ether. The ether layer is washed with water and dried,followed by evaporation of the ether to give 1 g. of crude oil of (1)3-methoxy-l7-hydr0Xy-8,14-secoestra l,3,5(l0),9(1l),l5- pentaen-l4-one.

(3) 3-methoxy-l7B-hydroxy-8,l4-secoestra-1,3,5-(l0),9(11),15-pentaen-l4-one 17-benzoate In 20 ml. of pyridine isdissolved 1 g. of the crude oil obtained in step (2), and 1.5 g. ofbenzoyl chloride is gradually added to the resultant solution underice-cooling, followed by stirring for 2 hours at room temperature. Thereaction mixture is poured into water, followed by ether extraction.After the ether layer is twice washed with 5% aqueous solution ofsulfonic acid, aqueous solution of sodium hydrogen carbonate and waterrespectively, it is subjected to evaporation of ether to obtain 1.5 g.of crude oil, which is subjected to column chromatography packed withsilica-gel employing benzene as the eluting solution. From the firsteluate, (i3methoxy-l75- hydroxy-8,l4-secoestra1,3,5(l0),9(1l),l5-pentaen-14- one l7-benzoate is crystallized and it isrecrystallized from methanol to give 0.4 g. of crystals melting atl101l2 C.

Elementary analysis.Calculated for C T-I 0), (percent): C, 77.59; H,6.51. Found (percent): C, 77.57; H, 6.53.

Ultraviolet absorption:

)tfifilf? me (e): 265 (19,700)

Infrared absorption:

1 13i? CHI-'1; 1713 Nuclear magnetic resonance spectrum (CCLQ: 8 values(p.p.m.):

(singlet3H, C13-CH3) 3.64 (singlet3H, O'CH 5.55 (tripletl=7 c.p.s., 1H,C -H) 5.87 (multipletlH, l7 a-H) 6.24 (quartet-1:6 c.p.s. and 17 c.p.s.,1H, C H) 6.3-6.6 (multiplet2H, C C -JH) 7.22 (doublet] =8 c.p.s., 1H, CH) 7.3-8.02 (multipletC I-I, H of ester aromatic ring) 9 (4)'-)3,l6-dimethoxyestra-1,3,5(10),8,14- pentaen-17 6-ol 17,B-benzoate 0.5g. of 17B-benzoyloxy-3-methoxy-8,14-secoestra-1,3, 5(10),9(11),15-pentaen-14-one is dissolved in 50 ml. of methanol,followed by the addition of 1 ml. of concentrated hydrochloric acid. Theresulting mixture is boiled for 5 minutes, at the end of which period itis poured into Water, followed by extracting with ether. The extract iswashed with sodium hydrogencarbonate solution and water in that order,and is dried, followed by evaporation of the other. The residue ispurified by chromatography with 20 g. of silica gel to yield*-)3,16-dimethoxyestra- 1,3,5(10),8,14-pentaen-17,8-o1 17fi-benzoate ascrystals melting at 142 to 144 C. Yield, 60%.

Elementary analysis.Calculated for C2qH23O4 (percent): C, 77.86; H,6.78. Found (percent): C, 77.75; H, 6.44.

Ultraviolet absorption:

Mill? y (e); 313 (27,400)

Infrared absorption:

v5.33? emf; 1723 Nuclear magnetic resonance spectrum (C01 6 values(p.p.m.):

1.02 (3H, C CH 3.30 (3H, -0011,) 3.70 (3H, C --OCH 4.66 (1H, multiplet,C -H) 5.17 (1H, doublet, C -H) 5.47 (1H, C H) 6.4-7.2 (3H, H of ring A)7.2-8.1 (5H, H of ester aromatic ring) (5) (i 3,16-dimethoxyestra-1,3,5,8- tetraen- 17,8-01 l7-benzoate To a solution of 0.2 g.(i)3,16-dimethoxyestra-1,3, 5(l0),8,14-pentaen-17;3-o1 l7-benzoate in 50ml. of dioxane is added 0.3 g. of Raney nickel, followed by shaking inhydrogen gas stream. When the absorption of the hydrogen is complete,the catalyst is filtered off, and the filtrate is concentrated underreduced pressure, whereupon about 0.2 g. of crystalline(i)3,l6-dimethoxyestra-l,3, 5(1=0),8-tetraenl7}3-ol l7-benzoate isobtained. On recrystallization from methanol, it turns into colorlessflakes melting at 155 to 157 C.

Elementary analysis.Calculated for C27H3004 percent): C, 77.48; H, 7.23.Found (percent): C, 77.16; H, 6.89.

Ultraviolet absorption:

nd mg 278 (13,300)

(6) (i 3, l 6-dimethoxyestra-1,3,5 10) -trien- 1718-01 A solution of 0.2g. of the +-)3,16-dimethoxyestra- 1,3,5,(10),8 tetraen 17,3-0117-benzoate, as prepared above, in 40 ml. tetrahydrofuran and 80 ml.liquid ammonia is cooled to 50 C. and 0.7 g. of potassium is added. Themixture is stirred for 2 hours, at the end of which period 0.5 g. ofammonium chloride is added. Then the reaction mixture is allowed tostand at room temperature so that ammonia is removed. Water is added tothe residue and the resulting mixture is then extracted with ether. Theextract is washed with water and dried, followed by evaporation of theether to give about 0.15 g. of crystalline (i 3, l6-dimethoxyestra- 1,3,5 10) -trien- 175-01. On recrystallization from a mixture of ether andhexane, it turns into crystals melting at 166 to 168 C.

10 Elementary analysis.-Calculated for C H O (percent): C, 75.91; H,8.92. Found (percent): C, 75.63; H, 8.75.

Ultraviolet absorption:

nth? m (e); 278 1901), 287 (1883) (7) (:)estrone 7 g. of pyridinehydrochloride is added to 0.15 g. of the(i)3,16-dimethoxyestra-1,3,5(10)-trien-17fl-ol and the resulting mixtureis heated at 200 to 220 C. for 1 hour in the presence of nitrogen gas.Then 30 ml. of 5% hydrochloric acid is added to the reaction mixtureunder stirring, followed by extraction with ether. The ether solution isextracted with lN-aqueous sodium hydroxide solution, and the extract ismade acidic with concentrated hydrochloric acid, followed by extractionwith ether.

The ether extract is washed with water, dried, and is subjected toevaporation of the ether to give 0.05 g. of (:)estrone as crystalsmelting at 240 C.

EXAMPLE 2 0.13 g. of 4-hydroxy-2-methylcyclopentane-1,3-dione isdissolved in 5 ml. of a 0.12% solution of potassium hydroxide inmethanol. To the solution is added a solution of 0.1 g. of6-methoxy-l-vinyl-l-tetralol in 5 ml. of methanol at the refluxtemperature, and the reflux is continued for a further 3 hours. Then,the reaction mixture is poured into water. The mixture is extracted withether, and the ether layer is washed with 10% aqueous potassiumhydroxide solution and water in that order, followed by drying. Thedried ether layer is subjected to evaporation of the ether to give oilyresidue, which is subjected to silica gel column chromatography to give0.04 g. of 3-methoxy- 8,14 secoestra-1,3,5(10),9,15-pentane-l4,7-dionein the form of pale yellowish crystal melting at 84 C. Thereafter, thesame reaction as Example 1 (2)-(7) is carried 0111;.

EXAMPLE 3 In 100 ml. of methanol is dissolved 5 g. of S-(2-(6-methoxy-l-tetraliden)ethyl)-thiuronium acetate, followed by the additionof 3 g. of 4-ethoxycarbonyloxy-2-methylcycloppentane-1,3-dione. Theresulting mixture is stirred at room temperature for 3 hours, at the endof which time the reaction mixture is poured into Water, followed byextracting with ether. After drying, the ether is distilled out,whereupon 3.0 g. of 3-n1ethoxy-8,14-secoestra-1,3,5(10),9,15-pentaene-14,17-dione is obtained as yellow crystalsmelting at 84" C. Thereafter, the same reaction as Example 1(2)(7) iscarried out.

EXAMPLE 4 1) (i)3,16-dimethoxyestra-1,3,5(10),8,14-pentaen- 17 {3-01 Inthe mixture of 7.5 ml. of methanol and 7.5 ml. of tetrahydrofuran isdissolved 0.3 g. of 3,16-dimethoxyestra- 1,3,5(10),8,14-pentaen-17,8-o117-benzoate, followed by addition of 4 ml. of 1 normal methanolicsolution of potassium hydroxide. The mixture is stirred for 1.5 hours atroom temperature and then the reaction solution is poured in to waterfollowed by extraction with ether. After the ether layer is washed withwater and dried, it is subjected to the evaporation of ether to obtain0.2 g. of (i)3,16-dimethoxyestra-1,3,5(10),8,14-pentaen-17,8-ol ascrystals melting at 143-8 C.

(2) )3,16-dimethoxyestra-1,3,5(10),8-tetraen-17,B-ol

Thus obtained (i)3,16-dimethylestra-1,3,5(10),8,14- pentaen-l7,B-ol istreated in the same manner as in Example 1 (5) to obtain(i)3,l6-dimethoxyestra-l,3,5(10), 8-tetraen-17,B-ol as crystals meltingat 1424 C. Yield:

Elementaly analysis.Calculated for C H O (percent): C, 76.40; H, 8.34.Found (percent): C, 76.16; H, 8.28.

11 12 The accompanying chart visualizes the total synthesis 4 carbonatoms)gonapoly(di, tri or tetra)eu-l7-one nuaccording to the invention.cleus, which comprises (1) the step of allowing a com- 4- /NH2 sc\ X-NH: OH (.I) 01 B. on

(1) (Ha) (11b) on OR OR R2 R2 R2 R2 OR l o o o R R R1 R1 on OR OR. R2 R2R2 NWOR4 MGR NWOB.

HMO R R (R==H or R) (R'=H or R) (R=H or R) (VII) 0 o 0 R: R R2 R2 Ellimi: i 31% (XII) What is claimed is: pound having a2-(Khydroxy-Y-tetralino) ethylene or 1. A process for preparing acompound having a 16- S-(2-(1-tetraliden) ethyl) thiuronium nucleus toreact (R O- group wherein R is alkoxy of up to 4 carbon with a compoundhaving a 4-hydroxy-2-(hydrocarbon atoms, phenyl, methylphenyl oralkanoyl having 2 to 4 group that is phenyl, benzyl or alkyl up to 4carbon carbon atoms)-17-(R COO- group wherein R is anatoms)cyclopentane-l,3dione nucleus to produce a comaliphatic oraromatic radical)-13-(hydrocarbon group pound having a 13-(hydrocarbongroup that is phenyl, that is phenyl, benzyl or alkyl of up to 4 carbonatoms) benzyl or alkyl up to 4 carbon atoms)-8,l4-secogonagona-1,3,S(l0),8,l4-pentaene nucleus which comprises1,3,5(10),9(il),15-pentaene-I4,l7-dione nucleus, (2) the bringing acompound having a 17-(R COO-- group step of subjecting so-obtainedcompound having a 13- wherein R is an aliphatic or aromaticradical)-13-(hydro- (hydrocarbon group that is phenyl, benzyl or alkylup to carbon group that is phenyl, benzyl or alkyl of up to 4 4 carbonatoms)-8,14-secogna-l,3,5(10),9(11),15-pc11- carbon atoms)8,14-secog0na-1,3,S(10),9(ll),l5-pentaene-14,l7-dione nucleus to selectivereduction of the taen-l4-one nucleus into contact with a dehydratingacid OX0 radical at the position 17 to produce a compound catalyst inthe presence of an alkanol of up to 4 carbon having a iii-(hydrocarbongroup that is phenyl, benzyl or atoms or phenol or cresol or an alkanoicacid having 2 alkyl up to 4 carbon atoms)-8,14-secogona-l,3,5(l0),9- to4 carbon atoms. (ll),5-pentaen-14-one-ol nucleus, (3) the step of allow-2. The process of claim 1 wherein the acid catalyst is ing so-obtainedcompound having a l7-hydroxy-13-(hyselected from the group consisting ofhydrochloric, hydrocarbon group that is phenyl, benzyl or alkyl up to 4drobromic, sulfuric, phosphoric and polyphosphoric acids, carbonatoms)-8,l4-secogna-l,3,5(l0),9(ll), 15-pentaenand anhydrides, hydrogensalts, partial esters and pyridine 14-one nucleus to react withacylating agent to produce a complexes thereof, methane-, ethane-,benzeneand tolucompound having a 17-(R COO group wherein R is anene-sulfonic acids, sulfonated styrene-type cation eX- aliphatic oraromatic radical)-13-(hydrocarbon group change resin, Lewis acids andsilica gel, and wherein R that is phenyl, benzyl or alkyl up to 4 carbonatoms)-8, is methyl, ethyl, phenyl or B-carboxyethyl.14-secogona-l,3,5(l0),9(l1),l5-pentaen-14-one nucleus,

3. A process for preparing a compound having a 13- (4) the step ofcontacting so-obtained compound having (hydrocarbon group that isphenyl, benzyl or alkyl up to a 17-(R COO- group wherein R is analiphatic or aromatic radica1)-13-(hydrocarbon group that is phenyl,benzyl or alkyl up to 4 carbon atoms)-8,14-secogona-1, 3,5(l),9(1l),15-pentaen-14-one nucleus with a dehydrating acid catalyst inthe presence of a member selected from the group consisting of analkanol of up to 4 carbon atoms, phenol, cresol or an alkanoic acidhaving 2 to 4 carbon atoms to produce a compound having a l6-(R O groupwherein R is alkoxy of up to 4 carbon atoms, phen yl, methylphenyl oralkanoyl having 2 to 4 carbon atoms)- 17-(R COO group wherein R is analiphatic or aromatic radical)-13-(hydrocarbon group that is phenyl,benzyl or alkyl up to 4 carbon atoms)gona-1,3,5(l0), 8,14-pentaenenucleus, (5) the step of subjecting so-obtained compound having a l6-(RO- group wherein R is alkoxy of up to 4 carbon atoms, phenyl,methylphenyl or alkanoyl having 2 to 4 carbon atoms)-l7-(R COO groupwherein R is an aliphatic or aromatic radical)-13 (hydrocarbon groupthat is phenyl, benzyl or alkyl up to 4 carbonatoms)gona-1,3,5(l0),8,l4,-pentaene nucleus, directly or afterhydrolysis, to selective reduction of the double bond at the position 14to produce a compound having a l6-(R O group wherein R is alkoxy of upto 4 carbon atoms, phenyl, methylphenyl or alkanoyl having 2 to 4 carbonatoms)-l7-(hydroxy or R COO- group wherein R is an aliphatic or aromaticradical)-l3-(hydrocarbon group that is phenyl, benzyl or alkyl up to 4carbon atoms)-gona-1,3,5(),8-tetraen-17-ol nucleus, and the step ofcontacting so-obtained compound having a 16-(R O group wherein R isalkoxy of up to 4 carbon atoms, phenyl, methylpenyl or alkanoyl having 2to 4 carbon atoms)-13-(hydrocarbon group that is phenyl, benzyl or alkylup to 4 carbon atoms)gona-1,3,5( 10), 8-tetraen-l7-ol nucleus, directlyor after acylation of 17- hydroxyl radical, or after selective reductionof the dou- 14 ble bond at the position 8, or the double bonds at theposition 8 and one of the aromatic ring, with a dealcoholating acidreagent.

4. The process of claim 3 wherein the acid catalyst is selected from thegroup consisting of hydrochloric, hydrobrornic, sulfuric, phosphoric andpolyphosphoric acids, and anhydrides, hydrogen salts, partial esters andpyridine complexes thereof, methane-, ethane-, benzeneandtoluene-sulfonic acids, sulfonated styrene-type cation exchange resin,Lewis acids and silica gel wherein R is methyl, ethyl, phenyl orfl-carboxyethyl and the dealcoholating acid reagent is selected from thegroup consisting of pyridine hydrochloride, quinoline hydrochloride,potassium hydrogen sulfate, hydrogen iodide, organic sulfonic acids,phosphoric anhydride, aluminum trichloride and boron trifiuoride.

5. 3,l6-dimet hoXyestra-1,3,5(l0),8,l4 pentaen 17,8- 01 17,8-benzoate.

6. 3,16-dimethoxyestra-1,3,5(10),8-tetraen-17 3-ol 17B- benzoate.

7. 3,16-dimeth0Xyestra-1,3,5 lO)-trien-17B-ol.

8. 3,16-dimethoxyestra-l,3,5(l0),8,l4-pentaen-17;8-ol.

9. 3,16-dirnethoXyestra-1,3,5 l0),8-tetraen-l7fl-ol.

References Cited UNITED STATES PATENTS 2,779,773 1/1957 Huffman 260-39753,336,347 8/1967 Engelfried et a1. 260--397.5

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

